Aging of multicellular organisms can lead to the loss of normal cardiac function, ultimately resulting in heart failure. Heart failure affects approximately 1% of individuals over 50 but over 5% of individuals over 75, and with the ongoing steep rise in the proportion of elderly individuals within our population, age-related heart failure is certain to become an increasingly prevalent health condition. Most age-related heart failure is in the setting of normal systolic function, and this is a condition often associated with cardiac hypertrophy (i.e. enlargement of heart tissue) and called “diastolic heart failure” (G, P. Aurigemma, N Engl J Med 355, 308 (Jul. 20, 2006)). Diastolic heart failure accounts for 40-60% of heart failure cases (G, P. Aurigemma, N Engl J Med 2006 355:308; S. A. Hunt et al., Circulation 2009 119:e391; D. W. Kitzman, K. R. Daniel, Clin Geriatr Itled 2007 23:83; J. C. Finerty, Physiol Rev 1952 32:277). The prognosis of diastolic heart failure may be as poor as systolic heart failure (G, P. Aurigemma, N Engl J Med 2006 355:308), with a 5-year risk of death after an initial heart failure hospitalization approaching that of common malignancies (D. E. Wright, et al. Science 2001 294:1933). Although much progress has been made in the treatment of systolic heart failure, with substantial improvements in outcome over the past two decades, progress in treatment of diastolic heart failure has been much more elusive (S. A. Hunt et al., Circulation 119, e391 (Apr. 14, 2009)). Indeed, one can argue that there are no specific therapies for patients who experience the ventricular “stiffening” associated with the diastolic dysfunction that accompanies aging (D. W. Kitzman, K. R. Daniel, Clin Geriatr Itled 23, 83 (February, 2007)). It is this clinical reality that may explain the observation that mortality is declining for systolic heart failure but not diastolic heart failure (J. C. Finerty, Physiol Rev 1952 32:277), and underscores the enormous clinical demand for new therapeutic strategies targeting diastolic failure.
Diastolic heart failure is a clinical syndrome that occurs in a variety of pathophysiologic settings, including long-standing hypertension, valvular disease such as aortic stenosis, genetic hypertrophic cardiomyopathy, and as a result of aging. These disparate etiologies converge with some common pathophysiologic threads, most obviously with cellular hypertrophy or increased diameter of cardiomyocytes; which translates into increased thickness of the heart wall without significantly reducing squeezing capacity (systolic function). Myocardial hypertrophy is an important contributor to the impairment in relaxation or increased stiffness that causes diastolic heart failure (A. J. Wagers, et al., Science 2002 297:2256).